Understanding the multiple biological aspects leading to myeloma

Boyle, Eileen M.; Davies, Faith E.; Leleu, Xavier; Morgan, Gareth J.

doi:10.3324/haematol.2013.097907

Cited by 24 publications

(24 citation statements)

References 118 publications

(133 reference statements)

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“…TNB-383B is a trivalent anti-BCMA x anti-CD3 BsAb, with a bivalent anti-BCMA arm (112). The BsAb has a silenced human IgG4 Fc region, with a 10-day half-life in cynomolgus monkeys (113). Preclinical studies testing the drug in BM samples from seven R/R MM patients showed that TNB-383B induced MM cell death, dose-dependent T cell activation, and less cytokine secretion than other BsAbs.…”

Section: Tnb-383bmentioning

confidence: 99%

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

et al. 2020

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Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological neoplasm in adults, comprising 1.8% of all cancers. With an annual incidence of ∼30,770 cases in the United States, MM has a high mortality rate, leading to 12,770 deaths per year. MM is a genetically complex, highly heterogeneous malignancy, with significant inter-and intra-patient clonal variability. Recent years have witnessed dramatic improvements in the diagnostics, classification, and treatment of MM. However, patients with high-risk disease have not yet benefited from therapeutic advances. Highrisk patients are often primary refractory to treatment or relapse early, ultimately resulting in progression toward aggressive end-stage MM, with associated extramedullary disease or plasma cell leukemia. Therefore, novel treatment modalities are needed to improve the outcomes of these patients. Bispecific antibodies (BsAbs) are immunotherapeutics that simultaneously target and thereby redirect effector immune cells to tumor cells. BsAbs have shown high efficacy in B cell malignancies, including refractory/relapsed acute lymphoblastic leukemia. Various BsAbs targeting MM-specific antigens such as B cell maturation antigen (BCMA), CD38, and CD138 are currently in pre-clinical and clinical development, with promising results. In this review, we outline these advances, focusing on BsAb drugs, their targets, and their potential to improve survival, especially for high-risk MM patients. In combination with current treatment strategies, BsAbs may pave the way toward a cure for MM.

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Section: Tnb-383bmentioning

confidence: 99%

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

et al. 2020

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“…A distinct feature of MM cells is the requirement for an intimate relation with the bone marrow microenvironment, where malignant plasma cells are nurtured in specialized niches that maintain their long-term survival and protect them from drug-induced apoptosis [11] . During myeloma development and disease progression, the bone marrow microenvironment plays a critical role in virtually all pathogenic aspects of this disease, such as survival, growth, differentiation, invasion/metastasis, and drug resistance of MM cells.…”

Section: And the Bone Marrow Microenvironmentmentioning

confidence: 99%

“…Again, IMiDs synergistically interact with dexamethasone to kill MM cells, which is consistent with numerous clinical findings [25] . More recently, anti-MM activity of IMiDs has also been related to alterations in epigenetic status of MM cells through targeting the bone marrow microenvironment [11] .…”

Section: Development Of Imids With Dual Actions Via Targeting the MM mentioning

confidence: 99%

Novel mechanisms of action for immunomodulatory drugs (IMiDs) against multiple myeloma: from a tragedy to a therapy

Dai¹,

Jin²,

Li³

et al. 2016

IJHT

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Thalidomide, a sedative to ease morning sickness in pregnant women, was banned more than a half century ago due to causing a severe birth defect known as phocomelia. However, the late discovery of its immunomodulatory properties have led to a new era in the treatment of Multiple Myeloma (MM), a fatal disease that back then had no effective therapy available. The recent development and FDA-accelerated approval of the second-and third-generation thalidomide analogs lenalidomide and pomalidomide to treat MM have led to a paradigm shift in standard of care of MM patients by introducing this novel class of anti-MM therapeutics, termed Immunomodulatory Drugs (IMiDs). Although IMiDs have tremendously improved survival of MM patients, their Mechanism Of Action (MOA) remains largely unknown until cereblon, a component of the E3 ubiquitin ligase complex CRL4 CRBN , was discovered as a primary target of IMiDs for both thalidomide teratogenicity and IMiD anti-MM activity. Furthermore, studies have also identified IKZF1 and IKZF3 as the downstream substrates and effectors of cereblon to mediate dual actions of IMiDs, targeting both the MM bone marrow microenvironment and MM cells themselves. These cutting-edge findings have not only tackled the long-lasting conundrum for MOAs of IMiDs but more importantly could lead to more precise use of these agents in the treatment of MM. This article summarizes the new insights into the MOAs of IMiDs as an anti-MM therapy, with a perspective on the existing issues and future directions in this field.

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“…The main characteristic of this B-cell malignancy is the monoclonal expansion of abnormal plasma cells in the bone marrow which results in heterogeneous manifestations of the disorder including bone pain and fractures, symptoms of inadequate hematopoiesis, hypercalcemia, hyperviscosity, renal failure, infections and peripheral neuropathy ( 1 , 2 ). Several chromosomal, genetic and epigenetic events have been known to contribute to plasma cell transformation as well as disease progression ( 3 ). The most significant epigenetic changes detected during the transformation of monoclonal gammopathy of undetermined significance (MGUS) to myeloma are global hypomethylation and gene-specific hypermethylation ( 3 ).…”

Section: Contextmentioning

confidence: 99%

“…Several chromosomal, genetic and epigenetic events have been known to contribute to plasma cell transformation as well as disease progression ( 3 ). The most significant epigenetic changes detected during the transformation of monoclonal gammopathy of undetermined significance (MGUS) to myeloma are global hypomethylation and gene-specific hypermethylation ( 3 ).…”

Section: Contextmentioning

confidence: 99%

Immunotherapy in Multiple Myeloma Using Cancer-Testis Antigens

Ghafouri‐Fard

Seifi‐Alan

Shams

et al. 2015

Iran J Cancer Preven

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Context:Multiple myeloma (MM) is a B-cell malignancy characterized by monoclonal expansion of abnormal plasma cells in the bone marrow. It accounts for 10% of hematological malignancies. Although patients respond to a wide range of anticancer modalities, relapse occurs in a significant number of the cases. Immunotherapeutic approaches have been evolved to tackle this problem. Cancer-testis antigens CTAs as a group of tumor-associated antigens are appropriate targets for cancer immunotherapy as they have restricted expression pattern in normal tissues except for testis which is an immune-privileged site. Expression of these antigens has been assessed in different malignancies including MM.Evidence Acquisition:We performed a computerized search of the MEDLINE/PubMed databases with key words: multiple myeloma, cancer-testis antigen, and cancer stem cell and immunotherapy.Results:Several CTAs including NY-ESO-1, MAGE and GAGE family have been shown to be expressed in MM patients. Cellular and humoral immune responses against these antigens have been detected in MM patients.Conclusions:The frequent and high expression level of CTAs in MM patients shows that these antigens can be applied as cancer biomarkers as well as targets for immunotherapy in these patients.

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Understanding the multiple biological aspects leading to myeloma

Cited by 24 publications

References 118 publications

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

Novel mechanisms of action for immunomodulatory drugs (IMiDs) against multiple myeloma: from a tragedy to a therapy

Immunotherapy in Multiple Myeloma Using Cancer-Testis Antigens

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